Elsevier

The Lancet

Volume 380, Issue 9842, 18–24 August 2012, Pages 660-667
The Lancet

Articles
Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(12)60953-2Get rights and content

Summary

Background

Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis.

Methods

We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV1) before bronchodilation, and change in total score on St George's respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493.

Findings

71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26–0·54; p<0·0001). Prebronchodilator FEV1 did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI −0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (–5·17 units) and placebo groups (–1·92 units; difference −3·25, 95% CI −7·21 to 0·72; p=0·108).

Interpretation

Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year.

Funding

Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.

Introduction

Bronchiectasis is a disorder characterised by neutrophilic airway inflammation, chronic bacterial infection, and recurrent pulmonary exacerbations.1 Patients with bronchiectasis can have a disabling cough with production of large amounts of sputum, progressive decline in lung function,2 impaired quality of life,3, 4 and increased mortality.5, 6 Exacerbations occur at rates of 1·5–6·5 per patient per year,7, 8 and are associated with an increased risk of admission and readmission to hospital, and high health-care costs.9

The prevalence of bronchiectasis in most adult populations worldwide is unknown. With the widespread availability of modern diagnostic techniques such as high-resolution CT scanning, bronchiectasis is increasingly being recognised. In the USA, the number of bronchiectasis-associated admissions increased by 2–3% per year between 1993 and 2006, and the mean annual rate of admission in this period was 16·5 per 100 000 people.9 A further study10 showed that the prevalence of bronchiectasis increased by 8·7% per year between 2000 and 2007.

Few evidence-based treatments are available for the prevention and management of exacerbations and more are urgently needed.11 Macrolide antibiotics have anti-inflammatory and immunomodulatory properties in addition to their antibacterial properties.12 In the Effectiveness of Macrolides in patients with BRonchiectasis using Azithromycin to Control Exacerbations (EMBRACE) trial, we tested whether azithromycin decreases the frequency of exacerbations, increases lung function, and improves health-related quality of life in patients with non-cystic fibrosis bronchiectasis.

Section snippets

Study design and participants

We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand between Feb 12, 2008, and Oct 15, 2009. Patients were eligible for inclusion in the study when they were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. All CT scans were reviewed centrally by one respiratory radiologist (DM) to verify the diagnosis of

Results

141 patients underwent randomisation and all patients received at least one dose of the assigned treatment (figure 1). Table 1 shows baseline characteristics and concomitant use of respiratory medications. Fewer patients in the azithromycin group than in the placebo group withdrew from the study prematurely (figure 1). We established from pill counts that patients adhered 97·9% of the time in the azithromycin group and 98·3% of the time in the placebo group.

42 event-based exacerbations were

Discussion

We have shown that azithromycin treatment for 6 months in patients with non-cystic fibrosis bronchiectasis significantly decreases the rate of event-based exacerbations and increases the time to the first event-based exacerbation compared with placebo. These benefits persisted for 6 months after completion of treatment.

Randomised trials of other macrolides for treatment of non-cystic fibrosis bronchiectasis16, 17, 18 have previously been undertaken (panel). Five studies in patients with cystic

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